Field of the Invention
The present invention relates to combination therapy for cancer with a WT1 peptide vaccine and temozolomide. The present invention also relates to a pharmaceutical composition comprising a WT1 peptide, characterized by being used in combination with temozolomide.
Background Art
WT1 gene (Wilms' tumor 1 gene) is a gene identified as a causative gene for Wilms' tumor that is a childhood renal cancer, and encodes a transcription factor having a zinc finger structure. WT1 gene was initially considered to be a tumor suppressor gene. However, subsequent studies revealed that it rather functioned as an oncogene in a hematopoietic organ tumor and a solid cancer.
It has been shown that the in vitro stimulation of peripheral blood mononuclear cells with a WT1 peptide induces cytotoxic T-lymphocytes (CTLs) specific for the peptide, which kill hematopoietic organ tumor or solid cancer cells endogenously expressing WT1. Various WT 1 peptides capable of inducing WT1-specific CTLs, which are expected to be used for cancer immunotherapy, have previously been identified (Patent Literatures 1 to 11). Phase I and phase II clinical trials for cancer immunotherapy using WT1 peptides have also been conducted (Non Patent Literatures 1 to 4).
The presence of helper T cells specific for a cancer antigen is reported to be important for the efficient induction of CTLs. Helper T cells are induced and activated by recognizing a complex of an MHC class II molecule in antigen-presenting cells and an antigen peptide to thereby promote the proliferation, differentiation, and maturation of B cells and subsets of other T cells. Therefore, it is considered to be useful in cancer immunotherapy to activate the immune system through the induction of helper T cells by an antigen peptide that binds to an MHC class II molecule; a plurality of WT1 peptides having such a function have also previously been reported (Patent Literatures 12 to 14 and Non Patent Literature 5).
Gliomas are primary brain tumors arise from glial cells. What are considered to be malignant among gliomas are glioblastoma and anaplastic astrocytoma, and glioblastoma is a tumor occurring most frequently and having high malignancy among primary brain tumors and is a poor-prognosis disease having a life expectancy of 12 to 14 months and a 5-year survival of 5%. Surgery is the first choice for the treatment of newly-diagnosed malignant glioma; however, it is standard therapy therefor to perform radiation therapy and the administration of temozolomide as a chemotherapeutic agent against postoperative residual tumor cells because the glioma shows a marked tendency for invasion and is difficult to completely remove. However, its therapeutic results are not satisfactory with a median overall survival (OS) of 14.6 months, a median progression-free survival (PFS) of 6.9 months, and a median 2-year survival of 26% (Non Patent Literature 6).
Most chemotherapeutic agents nonspecifically affect not only tumor cells but also normal cells at a proliferative phase, and lymphocytes proliferated and activated by antigen stimulation are also similarly affected. Therefore, the immune system of a patient receiving chemotherapy is considered to be suppressed; regarding the simultaneous combined use of chemotherapy and immunotherapy, concerns exist about deleterious effects of chemotherapy on CTLs, i.e., cell-killing effects on CTLs in addition to the same effects on cancer cells. No therapy involving the combined use of cancer peptide vaccine therapy and temozolomide has previously been reported.